14 Heme-regulated eIF2α Kinase

Abstract

Iron-deficiency anemia is one of the most prevalent human diseases and is characterized by hypochromic microcytic erythrocyctes (for review, see Fairbanks and Beutler 1983). This observation led to studies in the 1950s, which demonstrated that inorganic iron stimulates the synthesis of hemoglobin in immature erythroid cells (Kruh and Borsook 1956; Kassenaar et al. 1957; Morell et al. 1958). Further studies showed that heme, not iron per se, is required for protein synthesis in reticulocyte lysates, since the iron-chelating agent, desferrioxamine, does not block the stimulatory effect of heme (Bruns and London 1965; Grayzel et al. 1966). During the last step of heme biosynthesis, iron is incorporated into protoporphyrin by ferrochelatase to form heme. Consequently, iron deficiency leads to heme deficiency. Heme-iron accounts for the majority of the iron in the human body, and hemoglobin (the most abundant hemoprotein) contains as much as 70% of the total iron content of a normal adult. Thus, iron and heme play very important roles in hemoglobin synthesis and erythroid cell differentiation. In reticulocytes, iron deficiency causes inhibition of protein synthesis with disaggregation of polysomes, which can be prevented by the addition of iron or hemin (Waxman and Rabinovitz 1965Waxman and Rabinovitz 1966; Grayzel et al. 1966). This shutoff of protein synthesis is a result of the activation of the heme-regulated inhibitor (HRI), which is a heme-regulated eIF2α kinase (for review, see Chen 1993; Chen and London 1995).

HRI belongs to the family of eIF2α kinases. This family also includes the double-stranded RNA-dependent eIF2α kinase (PKR) (Chapter...